Catalent recently
launched FormProRxTM, an interactive web tool designed to help innovators
match formulations to drug delivery challenges. The following will discuss how FormProRx
allows users to assess multiple oral drug delivery technologies in order to establish
which may be the most appropriate for their molecule.

Recent estimates indicate
that up to 90% of drug candidates in pharma development pipelines are poorly soluble.
Based on the FDA’s biopharmaceutics classification system, which places pharmaceutical
agents in groups based on their solubility and permeability, up to 70% of all
NCEs are estimated to fall into Class II, with low aqueous solubility and high
intestinal membrane permeability, and up to 20% may be Class IV compounds, with
low aqueous solubility and low intestinal membrane permeability. The dilemma
facing scientists is to find new compounds that combine activity and acceptable
aqueous solubility and permeability for oral delivery. Given today’s pressures
to develop new drug products as quickly as possible, the result is often NCEs
that show promising activity but have either poor solubility or poor
permeability, or both.

A recent survey
conducted by Catalent indicated that 74% of formulation scientists claim to
have worked with compounds that are poorly soluble or permeable in the past
year. These scientists need to rapidly assess a variety of drug delivery and bioavailability
enhancement technologies if they are to meet the regulatory and performance
demands of clinicians running trials, as well as global commercial markets if
the drug ultimately gains approval. There is therefore a huge need for techniques
that facilitate this fast assessment of the advantages and disadvantages of all
available technologies if compounds

are to be advanced
into and through the clinic in a timely manner.

R&D teams at pharma
companies – or the contract development and research organizations they have
contracted to assist them – have a responsibility to use this rapid assessment
of formulation technologies as an opportunity to create value for patients,
payors and the industry alike. However, some may not consider all available
technologies when making their evaluations. This may lead to a program being
discontinued when there was a perfectly acceptable solution out there, if only they
had the time and technical resource/capability to look more widely. Indeed,
many drugs have failed in Phase II, and yet have been revitalized at a later stage,
either by an in-house development team or at another company with different
clinical goals or commercial aspirations, where scientists have looked more
widely for the optimal bioavailability enhancement or drug delivery technology.
Furthermore, given the length of time a team works on a single NCE or a formulation,
few formulators have the opportunity to gain a truly wide and deep knowledge of
all of the drug delivery options that are available to each development program.
They may be unaware – or inexperienced in – the perfect technique that would
greatly enhance the therapeutic benefit of their molecule, or enable them to
deliver it more efficiently.

One way in which a
pharma company can expand its horizons in this field is to partner with a specialist
organization whose focus is the application of bioavailability enhancement and
modern drug delivery technologies. These companies may have a wider view of
what is possible, enabling the pharma company’s own scientists to work in
partnership with them to solve complex drug development problems. A technology-driven
company that specializes in formulation will have that deep expertise in
product development. Importantly, they will also be well aware of the
additional challenges posed by scale-up through later clinical trial phases and
on to commercial quantities, and final manufacturing
processes – and have the experience required to suggest successful processes.

Simple tableting
techniques are not always effective, and technologies such as particle-size engineering,
hot melt extrusion, lipid-based systems, spray drying, matrix tablets, and
beads all offer potential benefits in specific formulation challenges. All of
these technologies require experience and expertise if these benefits are to be
fully realized. A technology-based formulation specialist will have already experienced
the impact of lab setbacks, project failures, and process difficulties, and learnt
the lessons these failures provided. Because they have seen projects fail, they
are well placed to recommend actions that will prevent failures, will have designed-in
program measures to fail weaker formulations at an earlier stage of development
and avoid unnecessary cost. In today’s budget-conscious environment, working in
partnership with one of these experienced specialists allows the right formulation
solution to be identified at a fraction of the cost – and a fraction of the risk
– than would be the case had they started from scratch in house. And, of course,
being able to access this wider range of formulation “tricks” should not only
save time and money, it will allow better treatments to be reliably supplied,
to the benefit of patients.

In early 2013,
Catalent launched the Catalent Applied Drug Delivery Institute, with the aim of
developing and promoting better formulation as a means for improving treatment
outcomes for patients. The Institute was created to harness the knowledge of
the world’s leading experts in drug development, delivery, and formulation, and
partner with pharma companies and academia in order to achieve these better treatments.
The Institute has already held a number of events in the US and Europe, with
headlines that encompass the challenge being discussed such as “Overcoming
Bioavailability Challenges”, and where scientists from both industry and
academia were brought together in an open forum to discuss challenges facing
the products in their pipelines, and the new technologies that might be able to
solve those challenges. Another activity the Institute has overseen was a
survey of more than 300 formulation scientists. This survey, run in 2013, was
designed to gain a greater understanding of the challenges that are currently
facing formulators who are looking to bring efficacious drugs to market
(Catalent Drug Delivery Survey 2013). The results clearly showed that numerous
technical concerns remain when looking to create ways to overcome solubility
and bioavailability challenges. The number one issue that came up time and
again in the responses received was that not only are formulation scientists
increasingly seeing poorly water-soluble compounds in their pipelines, they are
also more challenging in nature than was common in the past. The result is poor
bioavailability, and if a solution cannot be found, otherwise promising medicines
will almost certainly be lost.

To achieve acceptable
oral bioavailability, the most appropriate and stable form of the molecule must
first be identified, and then delivered at a predetermined rate to a specific
site in the body. A good example is the behavior of APIs in the gastrointestinal
tract. Some APIs that are not orally available in tablet form can be absorbed
through the buccal membranes if formulations that disintegrate rapidly can be
developed. The API’s physicochemical properties will determine which excipients
and manufacturing processes might be utilized to create an acceptable oral dosage
form. The challenge facing the industry is to develop a formulation and associated
manufacturing process that will meet all the necessary delivery criteria while
also meeting demands for a long shelf-life, minimal restrictions on storage (for
example, no requirement for refrigeration), and sufficient patent life to make
the product commercially viable. In addition, the process and materials used must
be optimized to ensure the cost of goods for the final dosage form is acceptable,
and does not greatly outweigh the improved treatment value offered to patients.

Catalent has developed
a patent-pending tool, FormProRx, which enables scientists to investigate how
different drug delivery technologies could be applied to problematic APIs,
based on the characteristics of the drug substance, and the desired properties
of the drug product. Drug discovery scientists have used concepts, such as
drug-likeness for many years, in an attempt to reduce the high attrition rates
many drug development programs face. Yet, there has still been a rise in the
number of molecules with higher molecular weights and higher lipophilicity
coming through the pipeline. Such molecules all too often have those solubility
and permeability problems baked into them because of their physical properties.
If formulators and process development scientists had a tool that was easy to
use and allowed them to make a quick assessment of all available technologies,
then it would be much easier to pinpoint whether a suitable formulation might
be available for any drug candidate, whether produced by in silico or
experimental means.

The tool allows
scientists to input the chemical characteristics of their molecule, and the
product specifications they are looking to achieve. The proprietary algorithm
produces dose form recommendations, based on 80 years of experience in bioavailability
enhancement and applied drug delivery for challenging molecules. Whether the product
is an NCE or a reformulation of an old treatment, the web-based tool will almost
always be able to suggest new approaches that might improve pharmacokinetics,
therapeutic profile, or even patient adherence.

The algorithm is
broken down into five steps. It is important to note that a “don’t know” answer
is possible in most of the steps, which allows the user to work through the
whole web tool, even if they are still in the very early stages of synthesis or
product development. While clearly a fuller picture of the options will be available
if as much information as possible is included, this will assist scientists in
making informed decisions about the direction their work should go in next.

In the first step,
the tool asks for the target product profile, which enables a number of
different release profiles and coating systems to be considered that might enable
the desired label claims to be achieved. Next, the tool gathers information on the molecule’s solubilityand permeability. The third step goesthrough the various physicochemicalproperties of the molecule, allowing thetool to assess the formulation challenges that might be
expected in achieving thedesired dosage form.
The mostimportant aspect of this set of
questionsis the molecule’s sensitivity to a
varietyof different forms of degradation. It
asksthe user to choose all of the mostcommon physical and chemicalconditions that apply in which theformation of impurities or degradationproducts would likely be most prevalent.These include hydrolysis, heat, liquidphase, oxidation, light, and moisture,and form the basis for the choice ofprocessing techniques that will beincluded in the final recommendation.

Fourth,
the tool goes throughquestions about expected dosageamounts, and handling classifications interms of its potency. Finally, informationis gathered about how the API will likelybe processed, for example milling orsalt formation. Optimal API processingcan be one of the most straightforwardand least costly approaches forenhancing solubility and bioavailability.However, exploiting all availableoptions requires an understanding of themolecule’s acid/base properties, as wellas its likely solubility and precipitationproperties in the different parts of thegastrointestinal tract.

As a
result of all this informationprovided by the scientist, the
algorithmcreates a set of drug delivery
optionsfor further investigation. Itsrecommendations are split into threegroups – best fit, potential, and not anoption. This gives the formulation teama starting point to direct theirinvestigations, saving them a good dealof time by discounting some of theoptions entirely, and pointing them inthe direction of the best potentialoptions first. It also provides a briefdescription of the drug deliverytechnique in order to facilitate thedesign of future experiments andvalidate the results. Suggestions it mightpresent include softgel technology,tablets, capsules (in either immediate-releaseor modified-release form), hot melt extrusion,
or fast-dissolve dose forms. In addition, a molecule profile isgenerated.
This includes a summary of the inputs as a reference that can be shared across
a team of scientists.

The
challenge for pharmaceutical companies is thus how to maximize the bioavailability
of molecules that demonstrate activity, but are often poorly soluble and/or
permeable invivo, by selection and careful utilization of the
optimal formulation and drug delivery technologies. With the development of new
drug delivery technologies and strategies for enhancing bioavailability,
companies can begin to think about the oral delivery of drugs that currently
have to be given via injection, like insulin or calcitonin. Tools like
FormProRx can assist in this process, by sorting through all the many potential
options and suggesting the best few, a process that should help accelerate a
molecule’s path to market.

Dr.
Kurt Nielsen hasserved asCatalent’s ChiefTechnologyOfficer
andSenior VicePresident -Innovation
andGrowth sinceFebruary 2010. Prior to joining Catalent,Dr.
Nielsen was with URL/MutualPharmaceutical Company in Pennsylvaniaas
Executive Vice President,Pharmaceuticals. In his role at
URL/Mutual,Mr. Nielsen devised the strategy and ledthe
execution for activities in the company’snew
product portfolio, employing a varietyof
business arrangements. Prior to that role,he was
Vice President of R&D. Beforejoining
URLMutual, Dr. Nielsen heldexecutive positions with TEVAPharmaceuticals
USA; McNeil ConsumerProducts; Energy Biosystems, Inc.; BachemBioscience;
and Hercules, Inc., ArcoChemical Company, and Chubb
NationalFoam. He earned his PhD in Chemistry fromVillanova
University and his BS in Chemistry